Synthesis of 2-aryl-1-naphthol derivatives via a tandem palladium catalyzed arylation and dehydrogenation

ABSTRACT

The present invention relates to a one-pot process for preparing a compound of formula I: I; by reacting a compound of formula II with a compound of formula III: in the presence of a suitable solvent, a suitable base, a palladium catalyst and a suitable ligand.

This application is 35 USC 371 of PCT/US01/42945, filed Nov. 15, 2001which claims the benefit of U.S. Provisional application No. 60/253,502filed Nov. 28, 2000.

BACKGROUND OF THE INVENTION

Naphthol compounds of the general formula:

are versatile intermediates to pharmaceutically active compounds (see,e.g., U.S. Pat. Nos. 5,916,916, 5,929,090 and 5,998,401).

According to the procedures described in the above mentioned patents,the naphthol intermediates are constructed via a four step sequencebeginning from an arylacetic acid. Said construct employs undesirablereagents in chemical processing such as aluminum chloride (AlCl₃) and2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) under strong basic and acidicconditions.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to a process for preparing a compound offormula I:

wherein:

R¹, R², R³ and R⁴ are independently H, OH or OPg where Pg is a hydroxyprotecting group;

which includes reacting a compound of formula II:

with a molar excess, relative to the compound of formula II, of acompound of formula III:

wherein Lg is a leaving group;in the presence of a suitable solvent, a suitable base, a palladiumcatalyst and a suitable ligand; at a temperature between 35° C. and thereflux temperature of the reaction mixture.

DETAILED DESCRIPTION OF THE INVENTION

General terms used in the description of chemical formulas bear theirusual meanings. For example, the term “C₁–C₆ alkyl” refers to astraight, branched or cyclic (in the case of C₃–C₆ alkyl) aliphaticalkyl chain of 1 to 6 carbon atoms including, methyl, ethyl, propyl,isopropyl, cyclopropyl, n-butyl, s-butyl, t-butyl, cyclobutyl, pentyl,cyclopentyl, n-hexyl, cyclohexyl and the like.

The term “hydroxy protecting group” is well known to those skilled inthe art. Representative hydroxy protecting groups can be found inGreene, et al., Protective Groups in Organic Synthesis, John Wiley &Sons, Inc., New York, N.Y. 1991. Such groups include benzyl, CO-phenyl,CO₂-phenyl, trialkylsilyl such as t-butyldimethylsilyl, C₁–C₆ alkyl,CO(C₁–C₆ alkyl), CO₂(C₁–C₆ alkyl), and SO₂(C₁–C₆ alkyl) where saidphenyl moiety is optionally substituted with C₁–C₄ alkyl.

The term “leaving group” refers to an atom, or group of atoms that inthe aggregate are capable of being activated to oxidative insertion bythe palladium catalyst, i.e., to the palladium (0) species. Examples ofsuch leaving groups include halides such as Cl, Br and I; sulfonates (agroup of the general formula OSO₂R⁵ where R⁵ is optionally substitutedC₁–C₆ alkyl or optionally substituted phenyl) such as methanesulfonate,trifluoromethanesulfonate or toluenesulfonate; and phosphonates (a groupof the general formula OPO(OR⁵)2 where R⁵ is C₁–C₆ alkyl or phenyl.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction. Suitable solvents include methylene chloride, chloroform,1,2-dichloroethane, diethyl ether, acetonitrile, ethyl acetate,1,3-dimethyl-2-imidazolidinone, 1,4-dioxane, tetrahydrofuran,dimethylformamide, toluene, chlorobenzene, dimethylsulfoxide,N-methylpyrrolidinone, dimethylacetamide, hexamethylphosphoramide,toluene, xylene, halophenyl solvents such as chlorobenzene, etheralsolvents such as glyme, diglyme and ethyleneglycol diether ether,mixtures thereof, and the like.

The term “suitable base” refers to a base that is capable of effecting adeprotonation of the hydrogen alpha to the ketone in the compound offormula II, i.e., a base that can provide an in situ enolate of theformula:

Examples of bases that can accomplish this enolization include alkylmetals (for example, n-butyl lithium, s-butyl lithium, and t-butyllithium or ethyl magnesium bromide and the like), metal amides such aslithium diisopropyl amide, potassium, lithium, or sodium salts ofdimethylsulfoxide or hexamethydisilazane, metal hydrides (for example,sodium, lithium, or potassium hydride), metal alkoxides (for example,sodium, lithium or potassium t-butoxide) or cesium carbonate.

The term “palladium catalyst” refers to a source of Pd(0). Suitablepalladium catalysts for use in the process of the present inventioninclude elemental palladium, salts and complexes of palladium, andpalladium on solid supports such as palladium on carbon or palladium onaluminum oxide.

The term “suitable ligand” refers to a suitable compound containing P,S, N, and C than can donate a pair of electrons to the palladiumcatalyst. Suitable ligands include alkyl or aryl phosphines such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triphenylphosphineand the like.

The process of the present invention consists of a two stage sequence.The first step of the process involves a palladium catalyzedalpha-arylation of tetralone II with a molar excess of the compound offormula III. The arylated product is then oxidized with the excessformula III compound serving as stoichiometric oxidant. This oxidationcan occur simultaneously or may be effected by raising the temperatureof the reaction mixture or by adding triphenyl phosphine to the reactionmixture. This novel process is illustrated in Scheme 1 below.

A compound of formula II may be added to a solution or suspension of asuitable base, such as sodium tert-butoxide, in a suitable solvent, suchas 1,4-dioxane in the presence of the formula III compound. A palladiumcatalyst, such as palladium acetate, and a suitable ligand, such asBINAP, may then be added to the reaction followed by stirring/agitationof the resulting mixture for a time and at a temperature sufficient tocomplete the coupling and oxidation reactions. The resulting compound offormula I may be isolated by standard techniques.

In general, the reactants may be combined at ambient temperature. Oncethe reactants are combined, the reactions (coupling and oxidation) aretypically performed at elevated temperatures with the coupling reactiongenerally requiring less heat. The coupling reaction is typicallyperformed between 35° C. and the reflux temperature of the reactionmixture. More typically, the coupling reaction is performed between 50°C. and 120° C. with a reaction temperature range of 60° C. to 100° C.being more typical. Once the coupling has been effected, the oxidationreaction generally requires additional heat to effect thetransformation. Therefore, the oxidation reaction is typically performedbetween 50° C. and the reflux temperature of the reaction mixture. Moretypically, the oxidation reaction is performed between 80° C. and 160°C. with a reaction temperature range of 90° C. to 110° C. being moretypical.

As an alternative to applying additional heat to the system, aphosphine, such as triphenylphosphine may be added to the coupledproduct mixture to promote the oxidation at temperatures more similar tothose required for the coupling reaction.

Typically, a molar excess of base (from 2 to about 6 equivalents,relative to the compound of formula II, is used. More typically, 3.0 toabout 6.0 equivalents are employed while most typically, 3.5 to about4.5 equivalents are employed. A molar excess of between 3.8 and 4.2 ismost preferred. A molar excess of the compound of formula III (1.01 toabout 4.0 equivalents), relative to the compound of formula II, istypically used. More typically, 1.01 to about 3.25 equivalents areemployed while most typically, 1.75 to about 2.5 equivalents areemployed. The palladium catalyst is employed catalytically (0.005–10mole percent) relative to the compound of formula II. More typically,0.05 to about 5 mole percent is employed while most typically, 0.5 toabout 1.5 mole percent is employed. The amount of ligand used in thepresent process is dependent upon the amount of palladium catalyst used.A monodentate ligand requires approximately 2 equivalents of ligandrelative to the palladium catalyst whereas a bidentate ligand wouldrequire only 1 equivalent.

The time required to effect the overall transformation will be dependentupon the temperature at which the reactions are run. Therefore, theprogress of the reactions should be monitored via conventionaltechniques, e.g., HPLC, to determine when the reactions aresubstantially complete. Monitoring the progress of chemical reactions iswell within the ordinarily skilled artisan's capability.

Preferred compounds of formula II for use in the present process arethose where R¹ is hydroxy, methoxy, isopropoxy or benzyloxy,particularly benzyloxy. Preferred compounds of formula III for use inthe present process are those where R² is hydrogen and R³ and R⁴ areindependently selected from H, benzyloxy, methoxy or isopropoxy. Thus,preferred products of the above reaction include, but are not limitedto, 1-hydroxy-2-(4-methoxyphenyl)-6-(methoxy)naphthalene,1-hydroxy-2-(4-methoxyphenyl)-6-(isopropoxy)naphthalene,1-hydroxy-2-(4-methoxyphenyl)-6-(benzyloxy)naphthalene,1-hydroxy-2-(4-methoxyphenyl)-6-(hydroxy)naphthalene,1-hydroxy-2-(4-ispropoxyphenyl)-6-(hydroxy)naphthalene,1-hydroxy-2-(4-benzyloxyphenyl)-6-(hydroxy)naphthalene,1-hydroxy-2-(4-isopropoxyphenyl)-6-(methoxy)naphthalene,1-hydroxy-2-(4-isopropoxyphenyl)-6-(isopropoxy)naphthalene,1-hydroxy-2-(4-isopropoxyphenyl)-6-(benzyloxy)naphthalene,1-hydroxy-2-(4-benzyloxyphenyl)-6-(methoxy)naphthalene,1-hydroxy-2-(4-benzyloxyphenyl)-6-(isopropoxy)naphthalene, and1-hydroxy-2-(4-benzyloxyphenyl)-6-(benzyloxy)naphthalene.

In a preferred embodiment, a compound of formula I may be used toprepare pharmaceutically useful compounds such as that described in U.S.Pat. No. 5,998,401, that is, a compound of formula IV:

wherein

R¹ and R⁴ are as described above;

R^(5a) is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, or 1-hexamethyleneimino; and

n is 2 or 3; and or a pharmaceutically acceptable salt thereof;

European Patent Application No. EP 0 826 679, that is, a compound offormula V:

wherein

n, R¹, R², R³ and R⁴ are as described above with the proviso that bothR³ and R⁴ cannot be hydrogen; and

R^(5b) is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or1-hexamethyleneimino; or a pharmaceutically acceptable salt or solvatethereof; and U.S. Pat. No. 5,929,090, that is,

a compound of formula VI

or a pharmaceutically acceptable salt thereof wherein

p is 1, 2, or 3;

R¹, R³ and R⁴ are as described above;

R^(5c) is selected from the group consisting of 1-piperidinyl,1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino,4-morpholino, dimethylamino, diethylamino, diisopropylamino, and1-hexamethyleneimino; and

-   -   X is absent or is selected from the group consisting of —C(O)—        and —SO₂—;        the teachings of which are herein incorporated by reference.        Methods for converting a compound of formula I to these and        other pharmaceutically useful compounds may be found in said        U.S. patents and patent applications.

In a particularly preferred embodiment, a compound of formula I may beused to prepare a compound of formula VII, VIII, and IX:

Compounds of formula II are known in the art and are generallycommercially available or are prepared by methods well known in the artfrom readily available starting materials.

EXAMPLES Example 11-Hydroxy-2-(4-methoxyphenyl)-6-(benzyloxy)naphthalene

Twelve liters of 1,4-dioxane were vacuum degassed and then combined withsodium tert-butoxide (1523 g, 15.84 mol), 4-bromoanisole (1845 g, 9.86mol) and 3,4-dihydro-6-(phenylmethoxy)-1(2H)-naphthalenone (1002 g, 3.97mol). The resulting red slurry was again degassed by pulling vacuum andpurging the system with nitrogen. Palladium acetate (8.90 g, 0.0396 mol)and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25.9 g, 0.0416 mol)were added and the mixture was heated to 70° C. After 2.5 hours thetemperature was increased to 100° C. and this temperature was maintainedfor an additional 5 hours. The mixture was allowed to cool to ambienttemperature before quenching with 6 liters of 3 M HCl. The layers wereallowed to separate and the aqueous phase was extracted with 2 liters ofethyl acetate. The organic phases were combined and dried with 500 g ofsodium sulfate then concentrated to a red solid. The solid was combinedwith 4 liters of toluene and stirred at 60° C. for 1 hour then cooled toambient temperature. The solids were collected by filtration, washedwith toluene and dried in vacuo to provide 564 g (40%) of the titlecompound. H¹ NMR (CDCl₃, 500 MHz) 8.20 (d, J=9.1 Hz, 1H), 7.50 (d, J=7.3Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.42 (t, J=7.3 Hz, 2H), 7.35 (m, 2H),7.29 (d, J=8.5 Hz, 1H), 7.25 (dd, J=2.5, 9.1 Hz, 1H), 7.20 (d, J=2.5,1H), 7.07 (d, J=8.7 Hz, 2H), 5.75 (s, 1H), 5.20 (s, 2H), 3.88 (s, 3H).

1. A process for preparing a compound of formula I:

wherein: R1, R2, R3 and R4 are independently H, OH or OPg where Pg is ahydroxy protecting group; which includes reacting a compound of formulaII:

with a molar excess, relative to the compound of formula II, of acompound of formula III:

wherein Lg is a leaving group; in the presence of a suitable solvent, asuitable base, a palladium catalyst and a suitable ligand; at atemperature between 35° C. and the reflux temperature of the reactionmixture.
 2. The process of claim 1 wherein the compound of formula II isa compound where R² is benzyloxy, methoxy or isopropoxy and the compoundof formula III is a compound where R² is hydrogen; and R³ and R⁴ areindependently H, benzyloxy, methoxy or isopropoxy.
 3. The process ofclaim 2 wherein the compound of formula II is a compound where R¹ isbenzyloxy and wherein the compound of formula m is a compound where R³is hydrogen and R⁴ is methoxy.
 4. The process of claim 3 wherein thesolvent is 1,4-dioxane, the base is sodium tert-butoxide, the palladiumcatalyst is palladium acetate, the ligand is2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and the temperature is thereflux temperature of the reaction mixture.
 5. In a process forpreparing a compound of formula IV:

wherein R¹ and R⁴ are independently H, OH or OPg where Pg is a hydroxyprotecting group; R^(5a) is 1-piperidinyl, 1-pyrrolidinyl,methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino,dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;and n is 2 or 3; and or a pharmaceutically acceptable salt thereof;which comprises the process of claim
 1. 6. The process of claim 5wherein the compound of formula IV is of the formula VII:


7. In a process for preparing a compound of formula V:

wherein R¹, R², R³ and R⁴ are independently H, OH or OPg where Pg is ahydroxy protecting group with the proviso that both R³ and R⁴ cannot behydrogen; n is 2 or 3; and R^(5b) is 1-piperidinyl, 1-pyrrolidinyl,methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino,dimethylamino, diethylamino, or 1-hexamethyleneimino; or apharmaceutically acceptable salt or solvate thereof; which comprises theprocess of claim
 1. 8. The process of claim 7 wherein the compound offormula V is of the formula VIII:


9. In a process for preparing a compound of formula VI:

or a pharmaceutically acceptable salt thereof wherein p is 1,2, or 3;R¹, R³ and R⁴ are independently H, OH or OPg where Pg is a hydroxyprotecting group; R^(5c) is selected from the group consisting of1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, and 1-hexamethyleneimino; and X is absent or isselected from the group consisting of —C(O)— and —SO₂—; which comprisesthe process of claim
 1. 10. The process of claim 9 wherein the compoundof formula VI is of the formula IX: